Cellular senescence and senescence‐associated secretory phenotype via the cGAS‐STING signaling pathway in cancer

Abstract Cellular senescence is a complex cell fate, often induced by stress or damage, that can be beneficial or deleterious, depending on the physiological context and age of the organism. A prominent feature of senescent cells is a multi-faceted senescence-associated secretory phenotype (SASP), which includes growth factors, cytokine and chemokines, growth factors, proteases, bioactive lipids and metabolites. Senescent cells increase with age in most, if not all, mammalian tissues. Through the use of transgenic mouse models, senescent cells are now known to causally drive numerous age-related pathologies, largely through the SASP. Eliminating senescent cells, genetically or through the use of senolytic/senomorphic agents, can improve the health span, at least in mice, and hold promise for extension to humans in the near future.

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Senescence-Associated Secretory Phenotype Suppression Mediated by Small-Sized Mesenchymal Stem Cells Delays Cellular Senescence through TLR2 and TLR5 Signaling

Cells ◽

10.3390/cells10010063 ◽

2021 ◽

Vol 10 (1) ◽

pp. 63

Author(s):

Ji Hye Kwon ◽

Miyeon Kim ◽

Soyoun Um ◽

Hyang Ju Lee ◽

Yun Kyung Bae ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cellular Senescence ◽

Small Cells ◽

Critical Determinant ◽

Senescent Phenotype ◽

Toll Like Receptor 2 ◽

Secretory Phenotype ◽

Major Factors

In order to provide a sufficient number of cells for clinical use, mesenchymal stem cells (MSCs) must be cultured for long-term expansion, which inevitably triggers cellular senescence. Although the small size of MSCs is known as a critical determinant of their fate, the main regulators of stem cell senescence and the underlying signaling have not been addressed. Umbilical cord blood-derived MSCs (UCB-MSCs) were obtained using size-isolation methods and then cultured with control or small cells to investigate the major factors that modulate MSC senescence. Cytokine array data suggested that the secretion of interukin-8 (IL-8) or growth-regulated oncogene-alpha (GROa) by senescent cells was markedly inhibited during incubation of small cells along with suppression of cognate receptor (C-X-C motif chemokine receptor2, CXCR2) via blockade of the autocrine/paracrine positive loop. Moreover, signaling via toll-like receptor 2 (TLR2) and TLR5, both pattern recognition receptors, drove cellular senescence of MSCs, but was inhibited in small cells. The activation of TLRs (2 and 5) through ligand treatment induced a senescent phenotype in small cells. Collectively, our data suggest that small cell from UCB-MSCs exhibit delayed cellular senescence by inhibiting the process of TLR signaling-mediated senescence-associated secretory phenotype (SASP) activation.

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Irradiation Accelerates Plaque Formation and Cellular Senescence in Flow‐Altered Carotid Arteries of Apolipoprotein E Knock‐Out Mice

Journal of the American Heart Association ◽

10.1161/jaha.120.020712 ◽

2021 ◽

Author(s):

Yu Yamamoto ◽

Manabu Minami ◽

Kazumichi Yoshida ◽

Manabu Nagata ◽

Takeshi Miyata ◽

...

Keyword(s):

Dna Damage ◽

Apolipoprotein E ◽

Cellular Senescence ◽

Carotid Arteries ◽

Kinase Inhibitors ◽

Mice Model ◽

Knock Out ◽

Post Operation ◽

Radiation Induced ◽

Secretory Phenotype

Background Chronic inflammation through cellular senescence, known as the senescence‐associated secretory phenotype, is a mechanism of various organ diseases, including atherosclerosis. Particularly, ionizing radiation (IR) contributes to cellular senescence by causing DNA damage. Although previous clinical studies have demonstrated that radiotherapy causes atherosclerosis as a long‐term side effect, the detailed mechanism is unclear. This study was conducted to investigate the relationship between radiation‐induced atherosclerosis and senescence‐associated secretory phenotype in murine carotid arteries. Methods and Results Partial ligation of the left carotid artery branches in 9‐week‐old male apolipoprotein E‐deficient mice was performed to induce atherosclerosis. The mice received total body irradiation at a dose of 6 Gy using gamma rays at 2 weeks post operation. We compared the samples collected 4 weeks after IR with unirradiated control samples. The IR and control groups presented pathologically progressive lesions in 90.9% and 72.3% of mice, respectively. Plaque volume, macrophage accumulation, and phenotype switching of vascular smooth muscle cells were advanced in the IR group. Irradiated samples showed increased persistent DNA damage response (53BP1 [p53 binding protein 1]), upregulated cyclin‐dependent kinase inhibitors (p16INK4a and p21), and elevated inflammatory chemokines expression (monocyte chemotactic protein‐1, keratinocyte‐derived chemokine, and macrophage inflammatory protein 2). Conclusions IR promoted plaque growth in murine carotid arteries. Our findings support the possibility that senescence‐associated secretory phenotype aggravates atherogenesis in irradiated artery. This mice model might contribute to mechanism elucidation of radiation‐induced atherosclerosis.

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TWIST1 controls cellular senescence and energy metabolism in mesenchymal stem cells

10.22203/ecm.v042a25 ◽

2021 ◽

Vol 42 ◽

pp. 401-414

Author(s):

C Voskamp ◽

◽

LA Anderson ◽

WJLM Koevoet ◽

S Barnhoorn ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cellular Senescence ◽

Extracellular Acidification ◽

Cell Lineages ◽

Knowing That ◽

Control Mscs ◽

Multiple Cell ◽

Cellular Bioenergetics ◽

Secretory Phenotype

Mesenchymal stem cells (MSCs) are promising cells for regenerative medicine therapies because they can differentiate towards multiple cell lineages. However, the occurrence of cellular senescence and the acquiring of the senescence-associated secretory phenotype (SASP) limit their clinical use. Since the transcription factor TWIST1 influences expansion of MSCs, its role in regulating cellular senescence was investigated. The present study demonstrated that silencing of TWIST1 in MSCs increased the occurrence of senescence, characterised by a SASP profile different from irradiation-induced senescent MSCs. Knowing that senescence alters cellular metabolism, cellular bioenergetics was monitored by using the Seahorse XF apparatus. Both TWIST1-silencing-induced and irradiation-induced senescent MSCs had a higher oxygen consumption rate compared to control MSCs, while TWIST1-silencing-induced senescent MSCs had a low extracellular acidification rate compared to irradiation-induced senescent MSCs. Overall, data indicated how TWIST1 regulation influenced senescence in MSCs and that TWIST1 silencing-induced senescence was characterised by a specific SASP profile and metabolic state.

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Elevated Levels of Cellular Senescence and Senescence-Associated Secretory Phenotype Markers in COPD Small Airway Epithelial Cells

10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a4014 ◽

2020 ◽

Author(s):

J. Baker ◽

P.S. Fenwick ◽

L.E. Donnelly ◽

P.J. Barnes

Keyword(s):

Epithelial Cells ◽

Cellular Senescence ◽

Airway Epithelial Cells ◽

Small Airway ◽

Airway Epithelial ◽

Secretory Phenotype ◽

Phenotype Markers ◽

Small Airway Epithelial Cells

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Cellular Senescence in the Treatment of Ovarian Cancer

International Journal of Gynecological Cancer ◽

10.1097/igc.0000000000001257 ◽

2018 ◽

Vol 28 (5) ◽

pp. 895-902 ◽

Cited By ~ 3

Author(s):

Zehua Wang ◽

Haiou Liu ◽

Congjian Xu

Keyword(s):

Ovarian Cancer ◽

Cellular Senescence ◽

Tumor Resistance ◽

Search Terms ◽

Intracellular Mechanism ◽

Pubmed Search ◽

Secretory Phenotype ◽

The One ◽

Cellular Dna ◽

Near Future

ObjectiveThis review aimed to update the research and development of cellular senescence in the treatment of ovarian cancer. We discussed the current mechanisms of senescence and the major biomarkers of senescence, especially the methods of cellular senescence in the treatment of ovarian cancer.Materials and MethodsWe collected all relevant studies in PubMed from 1995 to 2017. The search terms included senescence and cancer, senescence and ovarian cancer, senescence-associated secretory phenotype, ovarian cancer and chemotherapy, radiotherapy, or biotherapy. PubMed search with the key words senescence and ovarian cancer lists approximately 85 publications. After excluding the duplicated articles, we selected 68 articles most relevant to senescence and ovarian cancer in this review.ResultsCellular senescence plays a key role in various biological processes of ovarian cancer, which is closely related with the occurrence, development, and treatment of ovarian cancer. Cellular senescence on the one hand can reduce the dose of chemotherapy in ovarian cancer; on the other hand, it also can solve the problem of tumor resistance to apoptosis. Therefore, cellular senescence has been shown to be the third intracellular mechanism of ovarian cancer prevention followed by cellular DNA repair and apoptosis.ConclusionsIn the near future, cellular senescence therapy could be a powerful tool for ovarian cancer treatment.

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Anti-cancer effect of marchantin C via inducing lung cancer cellular senescence associated with less secretory phenotype

Biochimica et Biophysica Acta (BBA) - General Subjects ◽

10.1016/j.bbagen.2019.05.006 ◽

2019 ◽

Vol 1863 (10) ◽

pp. 1443-1457

Author(s):

Xiu-Lei Zhang ◽

Xiao-Tian Ji ◽

Bin Sun ◽

Li-Lin Qian ◽

Xue-Lei Hu ◽

...

Keyword(s):

Lung Cancer ◽

Cellular Senescence ◽

Anti Cancer ◽

Secretory Phenotype

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Lipid Players of Cellular Senescence

Metabolites ◽

10.3390/metabo10090339 ◽

2020 ◽

Vol 10 (9) ◽

pp. 339

Author(s):

Alec Millner ◽

G. Ekin Atilla-Gokcumen

Keyword(s):

Cellular Senescence ◽

Morphological Changes ◽

Surrounding Tissue ◽

Membrane Remodeling ◽

Protein Targets ◽

Current State ◽

New Findings ◽

Secretory Phenotype ◽

And Function ◽

Inflammatory Phenotypes

Lipids are emerging as key players of senescence. Here, we review the exciting new findings on the diverse roles of lipids in cellular senescence, most of which are enabled by the advancements in omics approaches. Senescence is a cellular process in which the cell undergoes growth arrest while retaining metabolic activity. At the organismal level, senescence contributes to organismal aging and has been linked to numerous diseases. Current research has documented that senescent cells exhibit global alterations in lipid composition, leading to extensive morphological changes through membrane remodeling. Moreover, senescent cells adopt a secretory phenotype, releasing various components to their environment that can affect the surrounding tissue and induce an inflammatory response. All of these changes are membrane and, thus, lipid related. Our work, and that of others, has revealed that fatty acids, sphingolipids, and glycerolipids are involved in the initiation and maintenance of senescence and its associated inflammatory components. These studies opened up an exciting frontier to investigate the deeper mechanistic understanding of the regulation and function of these lipids in senescence. In this review, we will provide a comprehensive snapshot of the current state of the field and share our enthusiasm for the prospect of potential lipid-related protein targets for small-molecule therapy in pathologies involving senescence and its related inflammatory phenotypes.

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Deciphering the mechanism for induction of senescence-associated secretory phenotype (SASP) and its role in ageing and cancer development

The Journal of Biochemistry ◽

10.1093/jb/mvz055 ◽

2019 ◽

Vol 166 (4) ◽

pp. 289-295 ◽

Cited By ~ 9

Author(s):

Naoko Ohtani

Keyword(s):

Immune Responses ◽

Cancer Progression ◽

Cellular Senescence ◽

Innate Immune ◽

Innate Immune Responses ◽

Cycle Arrest ◽

Secreted Factors ◽

Suppression Mechanism ◽

Secretory Phenotype ◽

Sting Pathway

Abstract Cellular senescence is an irreversible form of cell cycle arrest that can be induced by persistent DNA damage, and is well known to function as an important tumour suppression mechanism. Cellular senescence is detected in aged organisms; thus, it is also recognized as a hallmark of organismal ageing. Unlike apoptotic cells, senescent cells can survive for long periods of time. Recently, it has been shown that the late stage of senescent cells are capable of expressing a variety of secreted proteins such as cytokines, chemokines and proteases, and this condition is now known as senescence-associated secretory phenotype (SASP). These secreted factors are involved in myriad of physiological functions including tissue repair and clearance of damaged cells. Alternatively, these factors may promote detrimental effects, such as chronic inflammation or cancer progression, should the SASP persist. Recent scientific advances have indicated that innate immune responses, particularly involving the cGAS–STING pathway, trigger SASP induction. Therefore, developing a strategy to regulate SASP may provide scientific insights for the management of age-associated diseases and the implementation of healthy ageing in the future.

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Cellular senescence contributes to radiation-induced hyposalivation by affecting the stem/progenitor cell niche

Cell Death and Disease ◽

10.1038/s41419-020-03074-9 ◽

2020 ◽

Vol 11 (10) ◽

Cited By ~ 3

Author(s):

Xiaohong Peng ◽

Yi Wu ◽

Uilke Brouwer ◽

Thijmen van Vliet ◽

Boshi Wang ◽

...

Keyword(s):

Salivary Gland ◽

Cellular Senescence ◽

Progenitor Cell ◽

Tissue Degeneration ◽

Cycle Arrest ◽

Radiation Induced ◽

Secretory Phenotype ◽

Cell Niche ◽

Gland Function ◽

Formation Efficiency

Abstract Radiotherapy for head and neck cancer is associated with impairment of salivary gland function and consequent xerostomia, which has a devastating effect on the quality of life of the patients. The mechanism of radiation-induced salivary gland damage is not completely understood. Cellular senescence is a permanent state of cell cycle arrest accompanied by a secretory phenotype which contributes to inflammation and tissue deterioration. Genotoxic stresses, including radiation-induced DNA damage, are known to induce a senescence response. Here, we show that radiation induces cellular senescence preferentially in the salivary gland stem/progenitor cell niche of mouse models and patients. Similarly, salivary gland-derived organoids show increased expression of senescence markers and pro-inflammatory senescence-associated secretory phenotype (SASP) factors after radiation exposure. Clearance of senescent cells by selective removal of p16Ink4a-positive cells by the drug ganciclovir or the senolytic drug ABT263 lead to increased stem cell self-renewal capacity as measured by organoid formation efficiency. Additionally, pharmacological treatment with ABT263 in mice irradiated to the salivary glands mitigates tissue degeneration, thus preserving salivation. Our data suggest that senescence in the salivary gland stem/progenitor cell niche contributes to radiation-induced hyposalivation. Pharmacological targeting of senescent cells may represent a therapeutic strategy to prevent radiotherapy-induced xerostomia.

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